Sertraline hydrochloride is a known compound having the following structural formula:

Sertraline, in the form of its hydrochloride salt, is the active principle of the medicinal product known under the trademark Zoloft®, useful in the treatment of depression, obsessive-compulsive disorders, panic disorders and premature ejaculation.
Sertraline hydrochloride can exist in different crystalline forms which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
U.S. Pat. No. 4,536,518 (Pfizer Inc.) describes a synthesis of sertraline hydrochloride by treating an ethyl acetate/ether solution of the free base with gaseous hydrogen chloride. This patent does not refer to specific polymorphic crystalline forms of sertraline hydrochloride. In such case, its preparation provides for a very high diluition ratio, involving large amounts of solvent. This process also presents several problems regarding its industrial applicability, primarily due to the use of diethyl ether. Furthermore, in step c) of U.S. Pat. No. 4,536,518 hydrogenation on Pd/C is provided which may lead to dehalogenated products. As also mentioned in WO 02/102761 removing such impurities is usually quite difficult even if recrystallization of sertraline hydrochloride is carried out, so that previous recrystallization of sertraline mandelate is required, at times leading to dramatic loss of yields.
U.S. Pat. No. 5,248,699 (Pfizer Inc.) discloses 5 polymorphic forms of sertraline hydrochloride (I, II, III, IV and V), which can be characterized by single crystal x-ray analysis, powder x-ray diffraction, infra-red spectroscopy and differential scanning calorimetry.
According to U.S. Pat. No. 5,248,699, sertraline hydrochloride produced by the method of U.S. Pat. No. 4,536,518 has a crystalline form corresponding to form II.
U.S. Pat. No. 5,248,699 also reports that form II is produced by rapid crystallization of sertraline hydrochloride from an organic solvent, including isopropyl alcohol, hexane, acetone, methyl isobutyl ketone, glacial acetic acid and ethyl acetate. The preferential formation of form I, II or IV in an acidic solution of an organic solvent such as those listed above depends on the rapidity of crystallization, but crystallization kinetics and cooling time are not easily controlled in an industrial plant.
U.S. Pat. No. 5,248,699 also discloses methods for preparing sertraline hydrochloride form II from sertraline chloride form V or VI, such as granulation (in methanol or ethanol), reslurry in an organic solvent and crystallization in DMF or cyclohexanol.
U.S. Pat. No. 6,495,721 (Teva Pharm. Ind.) describes processes for making sertraline chloride form II comprising the steps of dissolving sertraline base or its mandelate salt in an organic solvent, selected from the group consisting of ethyl acetate, acetone, hexane, t-butyl-methyl ether, isopropyl alcohol, n-butanol, t-butanol, isobutanol, and cyclohexane, to form a solution; adding hydrogen chloride to the solution; heating the solution for a time sufficient to induce the formation of sertraline hydrochloride; and isolating sertraline hydrochloride form II.
Some of the examples of methods for the preparation of sertraline hydrochloride as described in U.S. Pat. No. 6,495,721 were reproduced for experimental purposes, particularly those according to examples 4 to 10 thereof. By following said examples, it was found that sertraline hydrochloride form II could not be obtained, at least in a reproducible manner and in sufficient yield, since in some cases form I or at most a mixture of form I and form II was actually obtained.
In particular, sertraline hydrochloride form I was obtained by following examples 4, 6, 7, 9, 10
Form II thereof was only obtained from examples 5 and 8 but remarkably mixed with form I, in a form II 75% yield and 60% yield, respectively.
Therefore, it could be concluded that the above teachings taken from U.S. Pat. No. 6,495,721 do not allow to obtain sertraline chloride form II on a reliable industrial scale production, due to the poor reproducibility of the preparation methods thereof and in any case to insufficient yields.
A purpose of the instant invention is to provide a suitable method for selectively preparing pure sertraline hydrochloride form II in high yield and in a reproducible manner on an industrial scale, by thus solving the problems involved in working the above prior art.